HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0333v1 199/2/243    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kogai, T. Articles by Brent, G. Search for Related Content PubMed PubMed Citation Articles by Kogai, T. Articles by Brent, G.

T Kogai, Medicine, UCLA/West LA VA, Los Angeles, 90073, United States
S Sajid-Crockett, Los Angeles, United States
L Newmarch, Los Angeles, United States
Y Liu, Los Angeles, United States
G Brent, Endocrinology Division W111 D, West Los Angeles VA Medical Center, Los Angeles, United States

Correspondence: Takahiko Kogai, Email: tkogai{at}ucla.edu

Abstract

Thyrotropin (TSH) stimulation of sodium iodide symporter (NIS) expression in thyroid cancer promotes radioiodine uptake and is required to deliver an effective treatment dose. Activation of the insulin/PI3K (phosphoinositide-3-kinase) signaling pathway in TSH-stimulated thyroid cells reduces NIS expression at the transcriptional level. We, therefore, investigated the effects of PI3K pathway inhibition on iodide uptake and NIS expression in rat thyroid cell lines and human papillary thyroid cancer cells. A PI3K inhibitor, LY294002, significantly enhanced iodide uptake in two rat thyroid cell lines, FRTL-5 and PCCL3. The induction of NIS mRNA by LY294002 occurred 6 hours after treatment, and was abolished by a translation inhibitor, cycloheximide. Expression of the transcription factor, Pax-8, which stimulates NIS expression, was significantly increased in PCCL3 cells after LY294002 treatment. Removal of insulin abrogated the stimulatory effects of LY294002 on NIS mRNA and protein expression, but not on iodide uptake. These findings suggest that PI3K pathway inhibition results in post-translational stimulation of NIS. Inhibition of the PI3K pathway also significantly increased iodide uptake (~3.5 fold) in BHP 2-7 papillary thyroid cancer cells (Ret/PTC1 positive), engineered to constitutively express NIS. Pharmacological inhibition of Akt, a factor stimulated by the PI3K pathway, increased exogenous NIS expression in BHP 2-7 as was seen with LY294002, but not increase the endogenous NIS expression in FRTL-5 cells. PI3K pathway inhibition increases functional NIS expression in rat thyroid cells and some papillary thyroid cancer cells by several mechanisms. PI3K inhibitors have the potential to increase radioiodide accumulation in some differentiated thyroid cancer.